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Recombinant Enzyme Fusion Protein for Lysosomal Storage Disorders

Award Information

Department of Health and Human Services
Award ID:
Program Year/Program:
2007 / SBIR
Agency Tracking Number:
Solicitation Year:
Solicitation Topic Code:
Solicitation Number:
Small Business Information
26679 Agoura Rd. #100 Calabasas, CA -
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Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Phase 2
Fiscal Year: 2007
Title: Recombinant Enzyme Fusion Protein for Lysosomal Storage Disorders
Agency: HHS
Contract: 2R44HD052303-02
Award Amount: $813,983.00


DESCRIPTION (provided by applicant): Zhang, Yun Abstract There are over 40 lysosomal storage disorders, and most of these diseases affect adversely the central nervous system (CNS). The mainstay of treatment is enzyme replacement therapy (ERT). However, ER T is not effective for the brain, because the enzymes do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. Without treatment of the CNS, the young patients are destined to progressive neurodegeneration and death. The li miting factor in the future treatment of these diseases is the transport of the enzyme across the BBB. Bypass of the BBB with direct injection into the brain is not effective, because only a small part of the brain is treated with a trans-cranial delivery system. Conversely, virtually all cells of the brain can be treated with a trans-vascular delivery system that enables the enzyme to cross the BBB following intravenous administration. A new approach to the BBB delivery of large molecules such as enzymes i s the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the missing recombinant enzyme is fused to a BBB molecular Trojan horse. The latter is a genetically engineered protein that is able to cr oss the human BBB by receptor- mediated transcytosis on endogenous BBB peptide transport systems. Pre-clinical studies show that a large enzyme with a molecular weight gt100,000 Daltons, can be delivered to brain via transport across the BBB, following att achment to a BBB receptor-specific Trojan horse. The present work will produce a novel fusion gene encoding a lysosomal enzyme and a genetically engineered molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-180 . The fusion gene will be incorporated in a eukaryotic expression vector followed by permanent transfection of cells. These phase II studies will enable production of a master cell bank and development of the purification and downstream processing of the f usion protein. Fusion proteins comprised of BBB targeting antibodies and recombinant enzymes could be therapeutic in the treatment of the brain in human lysosomal storage disorders. 1 Zhang, Yun Project Narrative Lysosomal storage disorders are serious inb orn errors of metabolism, and about 75% of the ~40 lysosomal storage disorders affect the brain. The mainstay of treatment is Enzyme Replacement Therapy (ERT). However, ERT is ineffective in the brain, because the enzymes do not cross the blood-brain barri er (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) retain high lysosomal enzyme activity. This novel drug, designated AGT-180, will be a model for the treatment of the brain for multiple genetic diseases. 1

Principal Investigator:

Yun Zhang

Business Contact:

Jennifer Yang
Small Business Information at Submission:


EIN/Tax ID: 770626715
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No